Charged linkers and their uses for conjugation
Cell binding agent-drug conjugates comprising phosphinate-based charged linkers and methods of using such linkers and conjugates are provided.
1. A charged linker of formula (I)
wherein:
Y represents a functional group selected from the group consisting of an unsubstituted or substituted N-hydroxysuccinimide ester, p-nitrophenyl ester, dinitrophenyl ester, pentafluorophenyl ester, pyridyldisulfide, nitropyridyldisulfide, unsubstituted maleimido, β-maleimidopropionamido, haloacetate and carboxylic acid halide;
Z is different from Y and represents a thiol, pyridyldisulfide, —ONH 2 , carboxy, aldehyde, ketone, azide, unsubstituted or substituted maleimido, haloacetyl, hydrazine, halogen, or hydroxy group;
M is H, Na, K, N + R 1 R 2 R 3 or a pharmaceutical salt thereof;
R 1 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 2 is absent;
R 3 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 4 , and R 5 , are the same or different and are absent, H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, or a combination thereof.
2. The charged linker of claim 1 , wherein Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido.
3. The charged linker of claim 1 , wherein Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido.
4. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 100.
5. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms.
6. The charged linker of claim 1 , wherein R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 100 or a linear alkyl having from 1 to 6 carbon atoms, and R 4 and R 5 are absent.
7. The charged linker of claim 1 , wherein R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, and R 4 and R 5 are absent.
8. The charged linker of claim 7 , wherein p is an integer from 1 to 24.
9. The charged linker of claim 1 , wherein M is H.
10. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, azide, or unsubstituted or substituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.
11. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.
12. The charged linker of claim 1 , wherein
Y represents an unsubstituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.
13. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, azide, or unsubstituted or substituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.
14. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 3 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.
15. The charged linker of claim 1 , wherein
Y represents an unsubstituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.
16. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000.